Impaired human hematopoiesis due to a cryptic intronic GATA1 splicing mutation
Impaired human hematopoiesis due to a cryptic intronic GATA1 splicing mutation
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DOI：
10.1084/jem.20181625
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发表时间：
2019-05-01
影响因子：
15.3
通讯作者：
Sankaran, Vijay G.
中科院分区：
文献类型：
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作者：
Abdulhay, Nour J.;Fiorini, Claudia;Sankaran, Vijay G.
对遗传性血液疾病的等位基因变异的研究为人类造血提供了重要的见解。大多数情况下，确定的致病性突变导致功能丧失或错义改变。然而，评估非编码变异的致病性可能具有挑战性。在这里，我们描述了两名不相关的患者，他们表现出不同的造血功能障碍和其他造血功能障碍，这些障碍与GATA1的含子突变有关，GATA1位于典型剪接受体位点上游24个核苷酸。功能研究表明，这种单核苷酸改变导致规范剪接减少，并增加了替代剪接受体位点的使用，从而导致部分内含子保留事件。由此产生的改变的GATA1在锌指的c端含有一个5个氨基酸的插入，没有可观察到的活性。总的来说，我们的研究结果表明，GATA1剪接的改变，降低了这种主转录因子的正常形式的水平，如何导致人类造血的明显变化。
Studies of allelic variation underlying genetic blood disorders have provided important insights into human hematopoiesis. Most often, the identified pathogenic mutations result in loss-of-function or missense changes. However, assessing the pathogenicity of noncoding variants can be challenging. Here, we characterize two unrelated patients with a distinct presentation of dyserythropoietic anemia and other impairments in hematopoiesis associated with an intronic mutation in GATA1 that is 24 nucleotides upstream of the canonical splice acceptor site. Functional studies demonstrate that this single-nucleotide alteration leads to reduced canonical splicing and increased use of an alternative splice acceptor site that causes a partial intron retention event. The resultant altered GATA1 contains a five-amino acid insertion at the C-terminus of the C-terminal zinc finger and has no observable activity. Collectively, our results demonstrate how altered splicing of GATA1, which reduces levels of the normal form of this master transcription factor, can result in distinct changes in human hematopoiesis.